IMWG Guidelines for the Management of Treatment-Emergent Peripheral Neuropathy in Multiple Myeloma (MM)

The incidence, symptoms, reversibility, and predisposing factors of treatment-emergent peripheral neuropathy (PN) vary among myeloma therapies. PN incidence is affected by treatment dose and schedule, by combinations of potentially neurotoxic agents, and by patient characteristics.

Strategies for managing PN include early and regular monitoring, dose modification, and treatment discontinuation.

Because there is no cure for drug-induced PN, prevention is a key strategy for preserving quality of life and future treatment options.

Following are evidence-based guidelines for preventing, assessing, and treating PN.

PREVENTION OF PN

The optimal prevention of treatment-induced PN in MM patients can be achieved with careful dose modification of the treatments that cause it, chiefly bortezomib and thalidomide.

Following is the IMWG new proposed evidence-based dose-modification guideline for bortezomib. Early and prompt use of these guidelines has been shown to lead to improvement of resolution of PN while maintaining therapeutic efficacy:

Grading is based upon the NCI Common Toxicity Criteria for Adverse Events: Neuropathy and Pain

Patients with prior bortezomib-induced PN should be retreated with appropriate caution, i.e., a lower dose or a once-weekly schedule.

Data in patents with relapsed MM demonstrate a substantial reduction in PN with the newly FDA-approved subcutaneous (subq) bortezomib. If dose reduction or weekly administration of IV bortezomib does not improve PN, subq bortezomib can be used.

Dose modification and discontinuation should also be used in cases of thalidomide-induced PN.

Given the irreversibility of thalidomide-induced PN, and the fact that the risk of thalidomide-induced PN increases with cumulative dose, thalidomide treatment should be discontinued once Grade 2 PN occurs, and restarted with 50% dose reduction upon resolution to Grade </= 1 if the risk-benefit ratio is favorable.

Patients with Grade 1 PN should have their thalidomide dose reduced by 50%.

During maintenance treatment, thalidomide dose should be reduced to 50 mg per day as soon as a patient has achieved a plateau.

Some studies have indicated that thalidomide use should be limited to 6 months, although treatment for 6-12 months may be feasible with low doses.

Topical preparations such as cocoa butter or menthol cream may be helpful.

ASSESSING/MONITORING PN

All MM patients who are to receive neurotoxic drugs should be clinically assessed for signs and symptoms of PN before treatment is initiated—especially those with baseline neuropathy—and throughout therapy.

Regular monitoring is also important post-transplant in patients who previously had PN. In a small number of these patients, symptoms can worsen even several months after transplant.

A neurologist can determine if the PN is treatment-emergent or myeloma-related by administering an electromyogram (EMG).

A neurologist can discern motor neuropathy from myopathy (muscle breakdown), which is mostly steroid-induced in MM patients.

TREATMENT OF PN

Interventions effective against one type of neuropathy may not be effective against another due to the different mechanisms and types of neuropathy: sensory, motor, or sensorimotor.

A neurologist may start and monitor treatment of PN using an anti-epileptic or antidepressant (gabapentin, pregabalin, amitriptyline, duloxetine) medication. (Most available meds are effective in only 25-50% of patients.)

A study evaluating acupuncture for the alleviation of chemotherapy-induced PN in MM patients is underway (NCT00891618).

Double-blind, placebo-controlled studies have suggested promising results with the topical combination of baclofen, amitriptyline, and ketamine in chemotherapy-induced PN.

Alpha lipoic acid (ALA) is approved in the European Union for diabetic neuropathy and has been shown to be effective against chemotherapy-related polyneuropathy in various cancers other than MM. Preliminary in vitro data suggest that ALA may reduce the anti-myeloma activity of bortezomib, but appropriate timing of ALA can prevent this inhibitory effect.

Neuro-rehabilitation through physical and occupational therapy can be considered for prospective evaluation in patients developing treatment-induced PN.

The following table lists potential supplemental interventions and their suggested doses, as currently used at the Dana-Farber Cancer Institute. There is a need for prospective evaluation of the effects of these agents in prevention and treatment of PN specifically associated with each MM therapy.